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Details for Patent: 6,268,533

Details for Patent: 6,268,533

Title:

Formoterol process

Abstract:

A method is disclosed for the preparation of optically pure isomers of formoterol by the reaction of an optically pure 4-benzyloxy-3-formamidostyrene oxide with an optically pure 4-methoxy-.alpha.-methyl-N-(phenylmethyl)benzeneethanamine followed by debenzylation. Useful intermediates in the process are also disclosed, as are the novel L-tartrate salt of R,R-formoterol and pharmaceutical compositions thereof.

(a) reducing 2-bromo-4'-RO-3'-nitroacetophenone with about one equivalent of a borane reagent in the presence of a catalytic amount of a single enantiomer of an oxazaborolidine reagent to produce substantially enantiomerically pure .alpha.-(bromomethyl)-4-RO-3-nitrobenzenemethanol

(b) reducing said .alpha.-(bromomethyl)-4-RO-3-nitrobenzenemethanol with hydrogen in the presence of a noble metal catalyst to produce an aniline; and

(c) formylating said aniline with formic acid and acetic anhydride.

12. A process according to claim 11 wherein said oxazaborolidine reagent is generated in situ from (1R,2S)-1-amino-2-indanol and two equivalents of borane reagent.

13. A process according to claim 11 wherein said noble metal catalyst is platinum and said oxazaborolidine is derived from cis 1-amino-2-indanol.

14. A process according to claim 11 wherein steps (b) and (c) are carried out without isolation of said aniline.

15. A process according to claim 11 wherein said single enantiomer of an oxazaborolidine is derived from (1R,2S)-1-amino-2-indanol, and said substantially enantiomerically pure .alpha.-(bromomethyl)-4-RO-3-nitrobenzenemethanol is R-.alpha.-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol.

16. A process for preparing a substantially enantiomerically pure salt of 4-methoxy-.alpha.-methyl-N-(phenylmethyl)benzeneethanamine comprising:

(a) reducing 4-methoxyphenyl acetone with hydrogen in the presence of a platinum catalyst and about 1 equivalent of benzylamine in methanol;

(b) adding about one equivalent of a single enantiomer of mandelic acid;

(c) heating to obtain a methanolic solution;

(d) cooling to obtain a crystalline solid phase; and

(e) recovering said crystalline solid from said methanolic solution.

17. A process according to claim 16 comprising the additional step of converting said crystalline solid from step (e) to a salt of an acid other than mandelic acid.

18. A process for preparing a compound of formula ##STR31##

comprising the sequential steps of:

(a) reducing 2-bromo-4'-benzyloxy-3'-nitroacetophenone with about one equivalent of a borane reagent in the presence of a catalytic amount of a single enantiomer of an oxazaborolidine derived from cis 1-amino-2-indanol to produce substantially enantiomerically pure .alpha.-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol: ##STR32##

(b) reducing said .alpha.-(bromomethyl)-4-phenylmethoxy-3-nitrobenzenemethanol with a source of hydrogen in the presence of a noble metal catalyst to produce an aniline;

(c) formylating said aniline with formic acid and acetic anhydride to produce a compound of formula ##STR33##

(d) combining said compound of formula ##STR34##

a compound of formula ##STR35##

wherein A.sup.- is an acid counter ion, and at least one equivalent of a base to produce a mixture comprising an epoxide and a free base;

(e) heating said mixture of an epoxide and a free base at a temperature sufficient to cause a reaction to produce a benzyl-protected aminoalcohol; and

(f) reducing said benzyl-protected aminoalcohol with hydrogen gas in the presence of a noble metal catalyst.

19. A compound of formula: ##STR36##

wherein each of R.sup.1, R.sup.2 and R.sup.3 is independently chosen from the group consisting of hydrogen, C.sub.1 to C.sub.6 -alkyl, C.sub.1 to C.sub.6 -alkoxyl, and halogen and R.sup.4 is --NO.sub.2, --NH.sub.2 or --NHCHO.

20. A compound according to claim 19 wherein all of R.sup.1, R.sup.2 and R.sup.3 are hydrogen.

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